Currently, a large number of methods have been utilized for chemically crosslinking hydrogels, including Michael addition reactions (e.g. Lutolf M P & Hubbell J A, 2003), radical crosslinking reactions (e.g. Hem D L & Hubbell J A (1998) Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing. J Biomed Mater Res 39(2):266-276) and self assembly (e.g. Cellesi F, Weber W, Fussenegger M, Hubbell J A, & Tirelli N (2004) Towards a fully synthetic substitute of alginate: Optimization of a thermal gelation/chemical cross-linking scheme (“tandem” gelation) for the production of beads and liquid-core capsules. Biotechnology and Bioengineering 88(6):740-749). Specific chemistries utilized include thiol-ene, thiol-yne, Huisgens cycloaddition, Diels Alder reaction, and Native Chemical Ligation (Nimmo, C. M.; Shoichet, M. S. Bioconjug Chem 2011, 22, 2199-2209).
Many of these hydrogels have unacceptable limitations, such as the chemistry used for gelation reacting with the payload being encapsulated. For example, in the case of Michael-addition-crosslinked hydrogels, the crosslinker used is a di-cysteine-containing molecule that can act as a reducing agent for proteins. Thus, proteins incorporated in these hydrogels may have comprimised activity. In the case of radically crosslinked gels, the radicals can decrease the viability of cells through reactions with DNA and proteins. In other cases, such as the Huisgens cycloaddition, the addition of a toxic metal, such as copper, is required.
Furthermore, in some cases the starting materials can be unstable to storage. For example, thiols may oxidize or form disulfides.
Needed in the art is a hydrogel with improved stability and therapeutic properties.